DESCRIPTION: The investigator proposes to use mucosal feline immunodeficiency virus (FIV) infection as a model to study the earliest stages of HIV/lentivirus pathogenesis and evaluate means to tip the initial virus:host balance in favor of the host. Building upon findings from the original grant period they will address four major issues which are difficult to resolve in HIV-infected people. 1) The first aim will define the pathway of entry by identifying the earliest target cells in the mucosal and regional lymph nodes during the first hours following vaginal, rectal and oral exposure of cats to pathogenic FIV. 2) The second aim will examine if early immune modulation toward a type 1 cytokine profile will alter progression of mucosal FIV infection. Characterization of cytokine mRNA expression in purified lymph node cell phenotypes will evaluate the ability of treatments designed to drive a type 1 response to alter cytokine profiles and disease progression. 3) The third aim will evaluate if selective pressure on the FIV genome over time are a function of env sequence subtype. Viral env and gag sequences will be studied in sequential PBMC and regional lymph node biopsies after mucosal and parenteral transmission of FIV subtypes A, B and C to determine the frequencies of synonymous and nonsynonymous substitutions. 4) Finally the investigator will use clone feline CCR5 and CXCR4 genes and clinical and cell culture adapted FIV isolates from clades A, B, and C to address the hypothesis that in vivo passaged isolates of FIV employ primarily a CC-chemokine receptor whereas lab culture adapted strains often employ CXC receptors and mucosal entry and initial virus expansion is determined by the receptor repertoire on mucosal cell phenotypes.